Compound A Crystal Forms for Pharmaceutical Purity

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Solution Overview

Problem

There is a lack of information on the existence and production methods for crystals of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (compound A), which has shown various therapeutic and preventive effects for multiple diseases, necessitating the development of a novel crystal form and a method for its production.

Innovation Solution

The development of three novel crystal forms (Form-I, Form-II, and Form-III) of compound A, characterized by specific diffraction peaks in X-ray powder diffraction spectra, along with a pharmaceutical composition containing these crystals, and a method for their production involving steps such as dissolution, cooling, and drying, using solvents like ethanol and methylethylketone.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If compound A is used as a therapeutic agent, then therapeutic effects are achieved, but lack of crystal form information and production methods limits industrial application

Engineering Contradiction:
Improvetherapeutic effect consistencyVSAvoidindustrial production capability
Core Design Contradiction:
ReliabilityVSEase of manufacture

Solution Approach 1:

The patent applies parameter changes by systematically varying crystallization conditions including solvent types (ethanol, methylethylketone, their mixtures), temperatures (cooling from room temperature to 0°C or lower), and concentrations to obtain different crystal forms of compound A. This enables reliable production of consistent therapeutic agents with defined physical properties.

Inventive Principle:
Principle #35Parameter changes

Solution Approach 2:

The patent utilizes phase transitions by dissolving compound A in hot solvent and then cooling the solution to induce crystallization. The phase change from dissolved state to crystalline state allows for purification and formation of stable crystal forms suitable for industrial manufacturing.

Inventive Principle:
Principle #36Phase transitions

2Ease of manufacture

If amorphous or impure compound A is used, then production is simpler, but quality and consistency of medicament bulk is compromised

Engineering Contradiction:
Improveproduction simplicityVSAvoidmedicament quality consistency
Core Design Contradiction:
Ease of manufactureVSManufacturing precision

Solution Approach 1:

The patent applies extraction by using solvent crystallization to separate pure compound A from impurities. The compound is dissolved in minimal hot solvent and then cooled, causing pure crystals to form while impurities remain in the mother liquor or are filtered off, thereby achieving both purification and quality consistency.

Inventive Principle:
Principle #2Taking out (Extraction)

Solution Approach 2:

The patent applies preliminary action by performing dissolution and crystallization steps before final formulation. The compound is pre-purified through controlled crystallization using specific solvents and temperature conditions, ensuring high purity and consistency before being processed into final medicinal products.

Inventive Principle:
Principle #10Preliminary action

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The novel crystal forms provide a high-quality medicament with consistent effects, easy industrial handling, and improved purity and impurity removal, suitable for therapeutic applications across a range of diseases, including cardiovascular, respiratory, and inflammatory conditions.

Implementation Method 1

dissolving 4.0 g of compound A in 40 mL of ethanol or methylethylketone under heating to prepare a saturated solution

Methodology Applied
Scientific EffectSolvation: Solvation

Implementation Method 2

cooling the solution to obtain novel crystal forms of compound A

Methodology Applied
Scientific EffectCrystallisation: Crystallisation

Implementation Method 3

drying the obtained crystals to high purity

Methodology Applied
Scientific EffectEvaporation: Evaporation

Data Source

PatentEP2447254B1crystals
Publication Date: 2017.12.06 NIPPON SHINYAKU CO LTD
  • EP2447254B1 patent drawingFigure 1~2
  • EP2447254B1 patent drawingFigure 3~4
  • EP2447254B1 patent drawingFigure 5

AI summary

[Problem] A main object of the present invention is to provide a novel crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (hereinafter referred to as "compound A"). [Means for Resolution] A Form-I crystal of compound A, showing diffraction peaks at 9.4 degrees, 9.8 degrees, 17.2 degrees and 19.4 degrees in the powder X-ray diffraction spectrum thereof. A Form-II crystal of compound A, showing diffraction peaks at 9.0 degrees, 12.9 degrees, 20.7 degrees and 22.6 degrees in the powder X-ray diffraction spectrum thereof. A Form-III crystal of compound A, showing diffraction peaks at 9.3 degrees, 9.7 degrees, 16.8 degrees, 20.6 degrees and 23.5 degrees in the powder X-ray diffraction spectrum thereof.